Pharmaceutical compositions comprising silica microspheres

ABSTRACT

Topical vaginal compositions are disclosed herein which include silica microspheres and an active ingredient in the amount of 0.001 to 15.0% w/w selected from estradiol, metronidazole, clindamycin, butoconazole, and combinations thereof. The topical compositions provide sustained release of the active ingredient so as to reduce skin irritation.

RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.14/551,155, filed Nov. 24, 2014, which is a continuation of U.S.application Ser. No. 11/783,895, filed Apr. 12, 2007, now U.S. Pat. No.8,920,821, issued Dec. 30, 2014, which claims the benefit of U.S.Provisional Application No. 60/791,902, filed Apr. 14, 2006, and U.S.Provisional Application No. 60/817,247, filed Jun. 29, 2006, which areall incorporated hereto by reference.

BACKGROUND

Many topical pharmaceutical products such as solids, semisolids(ointments, creams, gels), liquids and suspensions contain ingredientswhich may cause irritation and various inflammation symptoms whenapplied to the skin or mucosa.

The severity of irritation to the susceptible user may range fromsubclinical to mild to severe. Typical symptoms of irritation includeitching (pruritus), stinging, burning, tingling, “tightness,” erythema(redness) or edema (swelling). The irritation response may be due to thedirect effect on the skin of certain topical product ingredients. Manyactive ingredients used in topical products are known irritants or arepotentially irritating, for example, retinoids, benzoyl peroxide,5-flurouracil, hydroquinone and the like.

Retinoids are a group of compounds consisting of vitamin A and itsderivatives which are very sensitive to oxidative degradation andexposure to visible light. Retinoids are effective as keratolyticagents. They are used topically to retard and ameliorate photoaging offacial skin, to treat actinic keratosis, acne vulgaris, psoriasis andwarts. The main drawback of retinoids topical products, and moreparticularly of products including tretinoin, is skin irritation.

Hydroquinone is a reduced quinone, well-recognized as a skin-lighteningagent. When topically applied, it produces a reversible depigmentationof the skin by inhibiting the enzymatic oxidation of tyrosine to3,4-dihydroxyphenylalanine, as well as suppressing other metabolicprocesses of melanocytes. In a clinical setting, hydroquinone isemployed to treat hypermelanosis. Hydroquinone is considered an irritantin topical applications.

Benzoyl peroxide is an antibacterial agent with demonstrated activityagainst Propionibacterium acnes. This action, combined with the mildkeratolytic effect of benzoyl peroxide is believed to be responsible forits usefulness in acne. The main side effects of benzoyl peroxidetopical formulations are redness, dryness or peeling of skin, burningand itching, and swelling.

5-Fluorouracil is an antineoplastic antimetabolite. 5-Fluorouracilinterferes with the synthesis of deoxyribonucleic acid (DNA) and to alesser extent inhibits the formation of ribonucleic acid (RNA).5-Fluorouracil is used for topical treatment of multiple actinic orsolar keratoses. In the 5% strength it is also useful in the treatmentof superficial basal cell carcinomas when conventional methods areimpractical, such as with multiple lesions or difficult treatment sites.The use of compositions comprising 5-Fluorouracil may cause scaling,swelling, urticaria and skin rash.

Several attempts have been made to reduce the undesirable side-effectsof the above active ingredients. Thus, for example Retin-A Micro®(tretinoin) 0.1% gel, Differing (adapalene) gel, Efudex® (Valeant)(fluorouracil) solution and cream and EpiQuin™ Micro. However, none ofthese are products is completely satisfactory, so the search for abetter product is still on.

It will be advantageous to prepare a composition for topical applicationhaving good stability, which will reduce irritation of the skin ormucosa.

SUMMARY

In one aspect, pharmaceutical compositions, in particular sustainedrelease vaginal compositions, for topical application are disclosed. Thesustained release compositions include 0.001 to 15.0% w/w of an activeingredient selected from a steroid, an antibiotic, an antifungal, or anycombination thereof, and silica microspheres, formed prior to contactwith the active ingredient, impregnated with the active ingredient.Accordingly, some of the active ingredient is free in the composition,and the active ingredient impregnated in the silica microspheresprovides sustained release of the active ingredient. In one embodiment,the active ingredient is present as 0.001% to 5% w/w/of the composition,more preferably 0.001% to 2% w/w of the composition. In one embodiment,the silica microspheres have a mean microsphere size in the range of 0.5micron to 40 microns. In another embodiment, the silica microsphereshave a mean microsphere size in the range of 1 micron to 20 microns.

In one embodiment, the steroid is estradiol. In one embodiment, theantibiotic is metronidazole and/or clindamycin. In one embodiment, theantifungal is butoconazole.

In one embodiment, the composition is formulated as a foam or asemisolid form. The semisolid form includes a gel, a cream, a paste, alotion, an ointment, a shampoo, a semisolid powder or a suspension.

The composition may also include one or more of a solvent, apreservative, an emulsifier, an emollient or humectant, and water. Ifthe solvent is present, it may be selected from the group consisting ofisopropanol, oleic acid, glycerol monooleate, oleyl alcohol, propyleneglycol, isopropyl myristate, and combinations thereof.

In another aspect, methods of treatment of the vaginal area aredisclosed. The methods include providing a sustained release vaginalcomposition as discussed above and below that has 0.001 to 15% w/w of asteroid, an antibiotic, an antifungal, and combinations thereofimpregnated in silica microspheres, and applying the sustained releasevaginal composition to the vaginal area as a single dose when the activeingredient is an antifungal or once daily for at most 14 days when theactive ingredient is a steroid or an antibiotic. When the activeingredient is a steroid, estradiol, the method treats vulvar and vaginalatrophy. When the active ingredient is an antibiotic, metronidazoleand/or clindamycin, the method treats bacterial vaginosis and bacterialvaginal infections and/or vulvovaginal candidiasis. When the activeingredient is an antifungal, butoconazole, the method treatsvulvovaginal candidiasis.

BRIEF DESCRIPTION OF THE DRAWINGS

In the following detailed description, reference will be made to theannexed drawings, in which:

FIG. 1 is a graphical illustration of the release profile of acomposition comprising tretinoin through a synthetic membrane incomparison to the release profile of Retin-A Micro gel.

FIG. 2 shows a close-up view of a sample of the formulation includingthe silica microspheres and tretinoin according to Example 1.

DETAILED DESCRIPTION

The present invention provides a topical composition which releases theactive ingredient in a sustained manner to so as prevent irritation orinflammation caused by the active compound. This composition may be usedfor skin application as well as for mucosal, nasal, and/or vaginalapplication.

This invention relates in general to compositions comprising silicamicrospheres for topical application of pharmaceuticals. Suchcompositions are smooth and easy to spread and provide a non-tacky,velvety after-feel due to the presence of the silica microspheres.

In an embodiment of the invention, the composition is formulated in asemisolid or a liquid form, such as for example without being limited, agel, a cream, a lotion, a foam, a paste, an ointment, a shampoo, asuspension or a semisolid powder. In another embodiment, the compositionis formed as a spray or an aerosol. In another embodiment, thecomposition is formed as a suppository.

In an embodiment of the invention, this invention relates tocompositions for topical use comprising silica microspheres which areimpregnated with an active agent.

Throughout the application, “silica microspheres” means, silicon dioxidediscrete spherical particles ranging in average size from 0.5 to 40microns.

In an embodiment of the invention, the silica microspheres may range inaverage size from 1 to 20 microns.

The invention is based on the observation that formulations comprisingsilica microspheres afford optimal release of the active ingredient,according to the embodiments of the invention.

According to some embodiments of the invention, there are providedcompositions for topical application of a pharmaceutical active agent,which comprise silica microspheres with an active ingredient in amountof 0.01 to 15% w/w in a gel phase.

The active ingredient may be any active ingredient used for treatingskin or other topical disorders.

In some embodiments of the invention, the active ingredient may be forexample, without limitation, a vitamin, a keratolytic agent, a steroid,a non-steroidal anti-inflammatory drug, an antibiotic, a tranquilizer,an antihistaminic, an antifungal, an antibacterial, an antiviral, ananti-itching agent, a wart-treatment agent, a disinfectant, animmunosuppressant, an anticancer or a local anesthetic or combinationthereof.

In an embodiment of the invention, the composition may comprise anactive ingredient, which can be for example, without limitation, vitaminA, a retinoid, tretinoin, adapalene, tazarotene, hydroquinone, benzoylperoxide, 5-fluorouracil, azelaic acid or any combination thereof.

In another embodiment, the active ingredient is a steroid, anantibiotic, and/or an antifungal selected for treatment of vulvar andvaginal atrophy, bacterial vaginosis and bacterial vaginal infections,or antifungal local treatment for vulvovaginal candidiasis (an infectioncaused by Candida). One such suitable steroid is estradiol. Theantibiotic may be selected from metronidazole and/or clindamycin. Onesuitable antifungal is butoconazole. As noted above, in one embodiment,the composition comprises silica microspheres with an active ingredientin an amount of 0.01 to 15% w/w in the composition. However, with theseactive ingredient, the concentration may be even lower, such as 0.001 to15% w/w of the composition, more preferably 0.001 to 5% w/w of thecomposition, and even more preferably 0.001 to 2% w/w of thecomposition.

The composition of the invention may be used to treat skin disorders anddiseases, including atopic dermatitis, psoriasis, rosacea, cancer,actinic keratosis, acne, skin pigmentation and other types of skininflammations or viral, fungal or bacterial skin infections.

Depending upon whether the active ingredient is hydrophobic orhydrophilic, it will be present in an oily or aqueous phase,respectively.

In an embodiment of the invention, the retinoids may be used for thetreatment of acne. Retinoids may be also useful in treatment of skinphotoaging and sun damage. Many individuals who have had a good deal ofsun exposure will show the following gross cutaneous alterations:wrinkling, leatheriness, yellowing, looseness, roughness, dryness,mottling (hyperpigmentation) and various premalignant growths (oftensubclinical). These changes are most prominent in light-skinned personswho burn easily and tan poorly. These cumulative effects of sunlight areoften referred to as “photoaging” skin.

When considering the use of retinoids in skin care products, it isbelieved that certain retinoids such as retinol (Vitamin A alcohol),retinal (Vitamin A aldehyde) and retinyl esters such as retinyl acetateand retinyl palmitate would be suitable.

Due to retinoids' sensitivity to light and air, and their skinirritability, much attention in topical products containing suchcompounds is directed toward providing a composition which has aprolonged shelf life and can deliver active ingredients in slow-releasepattern, to prevent skin irritation.

In an embodiment of the invention, the composition comprises an activeingredient, which is a retinoic acid or a derivative thereof.

In another embodiment of the invention, the composition comprises activeingredient, which is tretinoin.

In an embodiment of the invention, the amount of the active ingredientis 0.04-0.3% w/w.

In an embodiment of the invention, the amount of the active ingredientis 0.075-0.125% w/w.

In an embodiment of the invention, the amount of the active ingredientis 0.1-1.0% w/w.

In an embodiment of the invention, the amount of the active ingredientis 1.0-15% w/w.

In an embodiment of the invention, the amount of the tretinoin may bebetween about 0.05-0.3% w/w.

In an embodiment of the invention, the active ingredient is benzoylperoxide. The concentration of the benzoyl peroxide may range betweenabout 3-9% w/w.

In an embodiment of the invention, the active ingredient ishydroquinone. The concentration of the hydroquinone may be about 4% w/w.

In an embodiment of the invention, the active ingredient is5-flurouracil. The concentration of the 5-flurouracil may be betweenabout 0.5-5% w/w.

In an embodiment of the invention, formulation may comprise about 6% to20% of an oily phase, excluding the active ingredient.

In an embodiment of the invention, formulation may comprise about 5% to10% of an oily phase excluding the active ingredient.

The microsphere size in the compositions of the invention is in the sizerange of about 0.5 to about 40 microns. In an embodiment of theinvention, the size range may be of about 1 to 20 microns.

In some embodiments of the invention, the composition may comprise agelling agent.

The gelling agent of the invention, may be without limitation, acellulose derivative such as methyl cellulose, carboxymethyl celluloseand carboxymethyl cellulose salts, hydroxymethyl cellulose,hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose, tri-blockcopolymers (Poloxamer 407, for example), xanthan gum, a carrageenan,pectin, a mannan, curdlan, chondroitin sulfate, starch, galactan,dermatan sulfate, glycogen, gum arabic, a heparan sulfate, hyaluronicacid, hyaluronate sodium, tragacanth gum, hydroxyethyl cyamoposis gum,carboxymethyl cyamoposis gum, cyamoposis gum, a dextran, keratosulfate,chitosan, a carboxymethyl chitin, an agar, etc. One or more of the abovemay be used in admixture, or can be blended with thickeners and/orwater-soluble polymers. Carbomer is an example of a thickening agent foruse in such formulations, as set forth in examples 6 and 7 below.

In an embodiment of the invention, the gelling agent may be in an amountbetween 0.5-20% w/w. In another embodiment of the invention, the gellingagent may be in an amount between 5-15% w/w.

In an embodiment of the invention, the amount of the gelling agent maybe 1-4% w/w. In another embodiment the amount may be 2.5% w/w.

In an embodiment of the invention the composition may further comprisesolvent.

Further, the composition may comprise an antioxidant.

Further, the composition may comprise an antimicrobial preservative.

Further, the composition may comprise an emulsifier.

Further, the composition may comprise an emollient, humectant and water.

Suitable solvents include, but are not limited to alcohol, isopropanol,oleic acid, glycerol monooleate, oleyl alcohol, propylene glycol,isopropyl myristate or any combination thereof.

In some embodiments of the invention, the solvent may be in an amount ofabout 3 to 20%. In another embodiment, the solvent may be in an amountof about 4 to 15%. In another embodiment the solvent may be in an amountof about 6 to 10%.

In an embodiment of the invention when the solvent is oleic acid, theamount of the oleic acid may be about 2 to 10%. In another embodiment ofthe invention, the amount of the oleic acid is between 3 to 8%. Inanother embodiment the amount of the oleic acid is between 3 to 6%.

In an embodiment of the invention when the solvent, is isopropanol. Theamount of the isopropanol may be about 2 to 20%. In another embodimentof the invention, the isopropanol may be in an amount of about 3 to 15%.In another embodiment the amount of the isopropanol may be between 4 to10%. In another embodiment, the amount of the isopropanol may be betweenabout 5-6%.

In an embodiment of the invention the active ingredient may be dissolvedby combination of oleic acid and isopropanol.

In addition, compositions of the invention may also compriseconventional additives such as preservatives and antioxidants.

Typical preservatives include sorbic acid, thimerosal, benzyl alcohol,benzoic acid, chlorbutanol, maleic acid and methyl, ethyl, propyl orbutyl parabens or any combination thereof.

In addition, compositions of the invention may also comprise a chelatingagent of a polyamine carboxylic acid such as ethylene diaminetetraacetic acid (“EDTA”), or a pharmaceutically acceptable saltthereof.

The antioxidant may be butylated hydroxytoluene (BHT), butylatedhydroxyanisole (BHA), alpha-tocopherol or alpha-tocopherol succinate,sodium ascorbate or any combination thereof.

In an embodiment of the invention, the antioxidant may be in an amountof about 0.001 to 1%. In another embodiment the antioxidant may be in anamount ranging from 0.01 to 0.1%. In another embodiment of theinvention, the antioxidant may be in an amount of about 0.01 to 0.05%.In another embodiment, the amount of the antioxidant is about 0.02%.

The antimicrobial preservative should be chosen so as to fit topicaladministration, and one skilled in the art can conduct tests toroutinely select specific antimicrobial preservative for this purpose.In an embodiment of the invention, the sorbic acid is in an amount ofabout 0.01 to 1%. In another embodiment the sorbic acid may be in anamount of about 0.02 to 0.5%. In another embodiment the sorbic acid maybe in an amount of about 0.05 to 0.2%. In another embodiment, the amountof the sorbic acid is about 0.1%.

The antimicrobial preservative may be but is not limited to benzylalcohol in an amount of about 0.1 to 5%. In another embodiment theamount of the benzyl alcohol may be of about 0.2 to 2%. In anotherembodiment the amount of the benzyl alcohol may be of about 0.5 to 1%.In another embodiment, the amount of the benzyl alcohol is about 0.8%.

In another embodiment, the preservative may be a paraben, for example,C₁-C₄ parabens. Parabens are useful antifungal preservative and slow thegrowth of many different kinds of bacteria, mold, and certain types ofyeast.

Suitable emulsifiers in this embodiment include, but are not limited to,tri-block copolymers (Poloxamer 407, Poloxamer 188), Polyoxyl stearates(Polyoxyethylene-20 stearate—Mirj 49, etc), Polysorbates (Tween 80,Tween 60 and Tween 20), Sorbitane fatty acid esters (Span 60 or Span80), POE alkyl ethers (Brij 97, etc.), POE alkylphenyl ethers (POEnonylphenyl ether, etc.), sucrose fatty acid ester.

The emulsifier may be Poloxamer 407 in an amount of about 0.2 to 5%. Inanother embodiment the emulsifier may be in an amount of about 0.2 to2%. In another embodiment the emulsifier may be in an amount of about0.5 to 1%. In another embodiment, the amount of the emulsifier is about0.5%.

The emollient or humectant should be chosen so as to suitable fortopical administration, and one skilled in the art can conduct tests toroutinely select specific viscosity modifier for this purpose. Suitableemollient or humectant include, but are not limited to glycerin,propylene glycol, cyclomethicone, dimethicone copolyol or anycombination thereof.

The emollient may be in an amount of about 1 to 30%. In anotherembodiment the amount of about 3 to 20%, preferably 4-15%.

The oily component without an active ingredient is typically present inan amount of about 10-30%, and may include oleic acid, isopropanol, BHT,sorbic acid.

In the following description and in the examples, concentrations will beindicated by wt % which denotes the concentration by weight of thecomponent per 100 units weight of entire composition. All indicatedconcentrations should be understood as standing each by itself, and arenot cumulative. It should be appreciated by the artisan, however, thatthere is some dependency between the concentrations of the components,e.g., higher concentrations of the oil will generally require higherconcentrations of the emulsifier and surfactant.

In an embodiment of the invention, concentrations of the components areas follows: about 2 to 25% oily phase solvent; about 0.2 to 2% of theemulsifier, with about 0.2 to 1% being particularly preferred; about0.01 to 1% for the antioxidant, with about 0.02 to 0.10% beingparticularly preferred; about 0.05 to 5% for the antimicrobialpreservative, with about 0.1 to 1% being particularly preferred. For atopical gel application, about 0.2 to 15% of the gelling or thickeningagent can be included.

In some embodiments of the invention there is provided a process for thepreparation of a topical composition comprising silica microspheres in agel preparation, about 0.05 to 20% w/w of a gelling agent, and an activeingredient in the amount of 0.01 to 0.5% w/w. The process comprises:mixing the gelling agent with water so as to form a gelling composition;adding emulsifier (Poloxamer 407 or Span 80) to the components of theoily phase; adding silica or silica suspended in water to the oily phaseto impregnate silica microspheres with an active compound; and mixingsaid oily phase with the gelling composition.

The formulation process of the invention may further comprise addingpreservatives and humectants to the resultant composition.

In an embodiment of the invention, the composition may comprise oleicacid 2-10% w/w, Isopropanol 2-20% w/w, Sorbic acid 0.01-1% w/w, activeingredient 0.01-10.0%, silica microspheres 0.2-5.5% w/w, carboxymethylcellulose sodium 0.5-4.0% w/w, glycerin 3-20% w/w, benzyl alcohol0.1-5.0% w/w, Poloxamer 407 0.2-20% w/w and purified water.

In another embodiment of the invention, the composition may compriseoleic acid 3-8% w/w, Isopropanol 3-15% w/w, butylated hydroxytoluene0.01-0.05% w/w, sorbic acid 0.02-1.0% w/w, active ingredient 0.01-10.0%,silica microspheres 0.2-1.5% w/w, carboxymethyl cellulose sodium1.0-3.0% w/w, benzyl alcohol 0.2-2.0% w/w, Poloxamer 407 0.2-15% w/w,glycerin 3-15% w/w, EDTA, and purified water.

In an embodiment of the invention, the composition may comprise oleicacid 4-6% w/w, isopropanol 5-10% w/w, butylated hydroxytoluene0.01-0.03% w/w, sorbic acid 0.05-0.2% w/w, active ingredient 0.01-4%w/w, silica microspheres 0.25-1.0% w/w, carboxymethyl cellulose sodium2.0-2.5% w/w, glycerin 3-15% w/w, benzyl alcohol 0.5-1.0% w/w, sodiumhydroxide or trolamine to adjust pH and purified water.

In an embodiment of the invention, the invention is directed to a methodfor treating acne vulgaris, the method comprising administering aneffective amount of the composition of the invention, wherein the activeingredient is tretinoin. The amount of the tretinoin may be 0.1%.

In an embodiment of the invention, the invention is directed to a methodfor depigmentation, the method comprising administering an effectiveamount of the composition of the invention, wherein the activeingredient is hydroquinone. The amount of the hydroquinone may be 4%.

In an embodiment of the invention, the invention is directed to a methodfor treating actinic keratoses, the method comprising administering aneffective amount of the composition of the invention, wherein the activeingredient is 5-fluorouracil. The amount of the 5-fluorouracil may be0.5-5%.

In an embodiment of the invention, the invention is directed to a methodfor treating actinic keratoses, the method comprising administering aneffective amount of the composition of the invention, wherein the activeingredient is benzoyl peroxide. The amount of the benzoyl peroxide maybe 3-12%. In an embodiment of the invention, the amount of the benzoylperoxide is up to and including 10%.

The invention is illustrated with reference to the above-mentionedexamples, which are to be construed in a strictly non-limiting manner.

EXAMPLES

Examples 1-4 are topical compositions comprising tretinoin. Ingredientsamounts are in weight percentages. The compositions were preparedaccording to the processes described in detail in the examples below. Itis noted that the following examples do not limit in any way the scopeof the present invention.

Example 1 A Composition Comprising Tretinoin as an Active Ingredient

Ingredients Concentration (w/w %) Oleic acid 5.00 Isopropanol 8.00 BHT(Butylated Hydroxytoluene) 0.02 Sorbic acid 0.10 Tretinoin 0.10 Silicamicrospheres 0.70 1 cellulose sodiumcarboxymethyl CMC Na 2.40 Glycerin5.00 Benzyl alcohol 0.80 Poloxamer 407 0.50 Water A. P 70.38 Water B. P7.00

The process for the preparation of the composition was carried out asfollows:

1. CMC Na (carboxymethyl cellulose sodium) was added to water A and wasstirred vigorously until gel was formed;2. Glycerin and benzyl alcohol were added to stage 1 and mixed for tenminutes;3. Oleic acid, isopropanol, BHT, sorbic acid, Poloxamer 407 andtretinoin were heated to 50° C. while stirring, until clear solution wasobtained. Then the solution was cooled to room temperature;4. Silica Microspheres in water B were added to the cooled oily phaseand resultant mixture was stirred for at least one hour;5. Stage 4 was added to the mixer and stirred for one hour under vacuum.

An opaque yellowish gel was obtained. A close-up view of the formulationincluding the silica microspheres is attached hereto as FIG. 2.

Example 2 A Composition Comprising Tretinoin as an Active Ingredient

Ingredients Concentration (w/w %) Oleic acid 4.00 Isopropanol 6.00 BHT(Butylated Hydroxytoluene) 0.02 Sorbic acid 0.10 Tretinoin 0.10 Silicamicrospheres 0.70 Natrosol (HEC) 1.50 Xanthan gum 0.80 Trolamine 1.20Benzyl alcohol 0.80 Glycerin 15.00 Water q.s. 100%

The process for the preparation of the composition was as follows:

1. Trolamine, Natrosol (HEC) and xanthan gum were added gradually to thewater while stirring at high speed using mixer propeller;2. The mixture of oleic acid, isopropanol, BHT, sorbic acid andtretinoin was heated to 50° C. while stirring then cooled to the roomtemperature;3. Silica microspheres were added to the stage 2 and the resultantmixture was stirred for at least one hour;4. Benzyl alcohol and Glycerin were added to stage 15. Stage 4 was added to the mixer reactor and stirred vigorously.

An opaque yellowish gel was obtained.

Example 3 A Composition Comprising Tretinoin as Active Ingredient

Ingredients Concentration (w/w %) Oleic acid 4.00 Isopropanol 5.00 BHT(Butylated Hydroxytoluene) 0.02 Sorbic acid 0.10 Tretinoin 0.10 Silicamicrospheres 0.50-1.00 Poloxamer 407 A 12.00-15.00 Poloxamer 407 B0.2-1.0 Benzyl alcohol 0.80 Glycerin 15.00  Sodium hydroxide, dilutedAdjust pH Water q.s. 100%

The process for the preparation of the composition was as follows:

1. Poloxamer 407 A was added to the water while stirring at high speedusing mixer propeller;2. The mixture of oleic acid, isopropanol, BHT, sorbic acid, Poloxamer Band tretinoin was heated to 50° C. while stirring and then was cooled tothe room temperature;3. Silica Microspheres were added to the stage 2 and resultant mixturewas stirred for at least one hour;4. Benzyl alcohol and glycerin were added to stage 1 and stirred;5. Stage 3 was added to the mixer reactor and stirred vigorously;6. Sodium hydroxide was added for pH adjustment.

An opaque yellowish gel was obtained.

Example 4 A Composition Comprising Tretinoin as Active Ingredient

Ingredient Concentration (w/w %) Oleic acid 5.00 Isopropanol 10.00 BHT(Butylated Hydroxytoluene) 0.02 Sorbic acid 0.10 Tretinoin 0.10 Silicamicrospheres 0.70 CMC Na (carboxymethyl cellulose sodium) 2.40 Natrosol(HBC) 0.50 Glycerin 5.00 Benzyl alcohol 0.80 Poloxamer 407 0.20 P. Waterq.s. 100%

The process for the preparation of the composition was as follows:

1. CMC Na (carboxymethyl cellulose sodium) and Natrosol (HEC) weredispersed in water until a clear gel was formed2. Glycerin and benzyl alcohol were added to stage 1 and mixed;3. Oleic acid, isopropanol, BHT, sorbic acid, Poloxamer 407 andtretinoin were heated to 50° C. while stirring until clear solution wasobtained. Then the solution was cooled to the room temperature;4. Silica Microspheres were added to the cooled oily phase and resultantmixture was stirred for at least one hour;5. Stage 4 was added to the stage 2 and stirred for one hour undervacuum.

An opaque yellowish gel was obtained.

Example 5 A Composition Comprising Hydroquinone as an Active Ingredient

Ingredients Concentration (w/w %) Oleic acid 3.00 Isopropanol 8.00 BHT(Butylated Hydroxytoluene) 0.02 Sorbic acid 0.10 Vitamin A 0.10Poloxamer 407 0.50 Hydroquinone 4.00 Silica microspheres A 1.00 Silicamicrospheres B 0.50 Balnose - CMC 2.00 EDTA 0.04 Benzyl alcohol 0.80Glycerin 5.00 Water A 30.34 Water B 45.00

The process for the preparation of the composition was as follows:

1. To water A the following components were added: EDTA, glycerin andhydroquinone. The mixture was heated to the 60° C. under stirring, andafter the mixture was clear, it was cooled to the 40° C.;2. Silica microspheres A were added to stage 1 and stirred;3. The mixture of oleic acid, isopropanol, BHT, sorbic acid, Poloxamer407 and Vitamin A was heated to 50° C. while stirring until allcomponents were dissolved;4. Silica microspheres B were added to stage 3 and stirred;5. Stage 4 was added to the stage 2 and stirred for at least one hour;6. Blanose (CMC) was added to water B and stirred by using a mixerpropeller for the complete dispersion;7. Benzyl alcohol was added to stage 6;8. Stage 7 was added to stage 5 and the mixture was homogenized.

Example 6

A composition comprising 10% Benzoyl peroxide (BPO) as activeingredient:

Ingredients Concentration (w/w %) Benzoyl peroxide (BPO) 10.00Ethoxydiglycol 19.50 Glycerin 8.00 Silica microspheres 5.50 Carbomer0.60 Imidazolidinyl Urea 0.30 PEG-40 Hydrogenated 0.20 Disodium EDTA0.10 Sodium Hydroxide 0.16 Water q.s. 100%

Example 7 A Composition Comprising 5% Benzoyl Peroxide (BPO) as ActiveIngredient

Ingredients Concentration (w/w %) Benzoyl peroxide (BPO) 5.00Ethoxydiglycol 9.90 Glycerin 8.00 Silica microspheres 2.50 Carbomer 0.60Imidazolidinyl Urea 0.30 PEG-40 Hydrogenated 0.20 Disodium EDTA 0.10Sodium Hydroxide 0.16 Water q.s. 100%

The process for the preparation of the compositions listed above was asfollows:

1. Disodium EDTA and Carbomer were added to the water and homogenized;2. Glycerin was added to stage 1 and the mixture was stirred;3. PED-40 hydrogenated castor oil was heated to 40° C. separately andafter clear liquid was obtained, it was added to stage 2;4. 20% solution of sodium hydroxide was added for neutralization;5. A solution of imidazolidinyl urea in water was added to stage 4;6. Benzoyl peroxide was added to ethoxydiglycol separately and passedthrough Fryma colloid mill, twice;7. Silica microspheres were added to the stage 6 and resultant mixturewas stirred;8. Stage 7 was added to stage 5 and the mixture was homogenized.

Example 8 A Composition Comprising Adapalene as an Active Ingredient

Ingredients Concentration (w/w %) Mineral oil 6.00 Isopropyl Myristate3.00 BHT (Butylated Hydroxytoluene) 0.02 Sorbic acid 0.10 Adapalene 0.10Silica microspheres 0.70 CMC Na (carboxymethyl cellulose sodium) 2.40Poloxamer 188 1.00 Benzyl alcohol 0.80 Propylene glycol 10.00 Water q.s.100%

Example 9 Release Rate of Tretinoin from the Tretinoin Gel Formulationof Example 1

To compare the release rate of Tretinoin from Retin-A Micro gelformulation versus tretinoin gel formulations with silica microspheres,an in-vitro test through a synthetic membrane (Supor 450) was performed.As is shown in FIG. 1, the release profile of the active compound fromthe formulation of Example 1 was identical to that of Tretinoin formRetin A-Micro formulation.

Example 10 Comparative Irritation Test in Rabbit (Draiz Test)

No erythema 0 Very slight erythema (barely perceptible) 1 Well-definederythema 2 Moderate to severe erythema 3 Severe erythema (beef redness)to slight eschar formation 4 (injuries in depth)

A 10-day Repeat Dermal Tolerance study in New Zealand White Rabbits isconducted to assess the dermal tolerance of tretinoin formulations(compositions of the present invention and brand) during which theinvention's formulations are applied repeatedly on the skin of rabbitsfor ten consecutive days. A quantity of 0.5 g of each test itemformulation is applied to the prepared area of skin and spread uniformlyon the skin to cover an approximately 6 cm² (2×3 cm) patch. The treatedpatches are then left open (un-occluded). The test item formulations areapplied each morning and, after a 4 hour contact period, all the treatedareas and untreated control areas are washed thoroughly with de-ionizedwater in order to remove the test item residue. The treatment isperformed for 10 consecutive days. The skin reaction is assessedaccording to the numerical scoring system of Draize et. al (1944), asdefined in the following tables:

1. Erythema and Eschar Formation (Max Possible Score—4)

No edema 0 Very slight edema (barely perceptible) 1 Slight edema (edgesof area well defined by definite raising) 2 Moderate edema (raisedapproximately 1 mm) 3 Severe edema (raised more than 1 mm and extendingbeyond 4 area of exposure)

Two methods are used to evaluate the irritation potential of thecompositions of the present invention and brand:

The mean scores of all the rabbits for erythema and edema, for all tendays of treatment and three days post treatment, are added upseparately, and the highest mean score is used to calculate theirritation potential of the test item.

The skin scores of all the rabbits are added up and divided by the totalnumber of observations, to arrive at the mean; this is then used tocalculate the irritation potential of the test item.

Examples 11-14 are vaginal formulations comprising preformed silicamicrospheres, formed prior to contact with the active ingredient, areimpregnated with the active ingredient, which leaves some of the activeingredient free in the composition as shown in FIG. 2. The activeingredient that is impregnated in the silica microspheres providesustained release of the active ingredient. The impregnation of theactive ingredient in the silica microspheres may be carried out similarto the procedures set forth in Examples 5 or 7, selecting the one thatis most appropriate. Any percentages expressed herein are understood tobe wt/wt of the composition, even if not expressly stated.

Example 11 Treatment for Bacterial Vaginosis and Bacterial VaginalInfections

Name Composition (% w/w) Metronidazole 0.75 Edetate Disodium Dihydrate0.05 Propylene Glycol 3.0 Methylparaben 0.08 Propylparaben 0.02 Carbomer2.0 Sodium Hydroxide 0.1 Silicon dioxide 0.25-1.0 Purified Water q.s.100 (94.0) Total 100

A comparative of the formulation of Example 11 against METROGEL® vaginalcream (1%, once daily for 5 days), a commercially available vaginalcream by Galderma Laboratories, L.P., shows that the formulation ofExample 11 has a lower concentration, for example 0.75%. Moreover, theuse of the porous, preformed silica microspheres enables a shortertreatment period because of the sustained release of the activeingredient. The expected treatment with the formulation of Example 11 isonce daily for 3 days. Two days less than the treatment cycle forMETROGEL® vaginal cream. Moreover, the formulation of Example 11 hasbio-adhesive characteristics generally attributed to the presence of theCarbomer, which helps maintain the formulation at the area to betreated. For example, when topically applied within the vaginal, theformulation of Example 11 has reduced leakage, which is a benefit to theuser.

A comparison of the formulation of Example 11 to NUVESSA™ metronidazolevaginal gel (1.3%, single application only) by Allegan again revealsthat a lower concentration of the active can be used when impregnated inthe porous, preformed silica microspheres, for example 0.75%.

Example 12 Treatment for Bacterial Vaginosis and Bacterial VaginalInfections and/or Vulvovaginal Candidiasis

Name Composition (% w/w) Clindamycin Phosphate 1.0-2.0 Edetate DisodiumDihydrate 0.05 Propylene Glycol 3.0 Methylparaben 0.08 Propylparaben0.02 Carbomer 2.0 Sodium Hydroxide 0.1 Silicon dioxide 0.25-1.0 Purified Water q.s. 100 (94.0) Total 100

A comparative study against CLINDESSE® vaginal cream (2%, singleapplication dose) by Perrigo Company plc was compared to the formulationof Example 12. The impregnation of the clindamycin in the porous,preformed silica microspheres enabled for the option of less activeingredient, for example, 1.75% and 1.5%. The expected treatment with theformulation of Example 12 is also a single dose.

Example 13 Treatment for Vulvar and Vaginal Atrophy

Name Composition (% w/w) Estradiol 0.005-0.015 Polycarbofil 2.25Glycerin 14 Mineral Oil 4.5 Carbomer 1.5 Sorbic Acid 0.09 HydrogenatedPalm Oil 1.12 Silicon dioxide 0.25-1.0  NaOH q.s. Purified Water q.s.Total 100

A comparative study against ESTRACE® cream (0.01% estradiol), acommercially available vaginal cream by Allergan was compared to theformulation of Example 13. The impregnation of the estradiol in theporous, preformed silica microspheres enables use of less activeingredient, for example 0.005% estradiol and 0.0075% estradiol,respectively, for separate trials. The recommended dose for ESTRACE®cream is once daily for 14 to 28 days. The expected treatment with theformulation of Example 13 is one daily for 7 to 10 days.

Example 14 Treatment for Vulvovaginal Candidiasis

Name Composition (% w/w) Butoconazole Nitrate 1.5-2.0 Cetyl Alcohol 15Glyceryl Stearate and PEG-100 Stearate 5 Methylparaben 0.08Propylparaben 0.02 Mineral Oil 10 Polysorbate 60 5.0 Propylene Glycol20.0 Sorbitan Monostearate 5.0 Silicon dioxide 0.25-1.0  Stearyl alcohol4 Purified Water q.s. Total 100

A comparative study against GYNAZOLE 1® vaginal cream (2%, singleapplication dose) by Perrigo Company plc was compared to the formulationof Example 14. The impregnation of the butoconazole in the porous,preformed silica microspheres enabled for the option of less activeingredient, for example, 1.75% and 1.5%. The expected treatment with theformulation of Example 14 is also a single dose.

The advantages of the vaginal compositions disclosed herein includereduced skin irritation because of the extended release characteristicsprovided by the preformed, porous silica microspheres. The porous silicamicrospheres also enable a lower concentration of active ingredient withbetter efficacy, often over a shorter treatment cycle. In most caseswhere more than a single application is recommended, the formulationsdisclosed herein can reduce the treatment cycle by 2 days to 18 days,depending upon the commercially available product's recommendedtreatment cycle.

What is claimed is:
 1. A sustained release vaginal composition fortopical application comprising: 0.001 to 15.0% w/w of an activeingredient selected from a steroid, an antibiotic, an antifungal, andcombinations thereof; and silica microspheres, formed prior to contactwith the active ingredient, impregnated with the active ingredient. 2.The sustained release composition of claim 1, wherein some of the activeingredient is free in the composition, and the active ingredientimpregnated in the silica microspheres provides sustained release of theactive ingredient.
 3. The sustained release composition of claim 1,wherein the active ingredient is present as 0.001 to 5% w/w of thecomposition.
 4. The sustained release composition of claim 1, whereinthe steroid is estradiol, the antibiotic is metronidazole andclindamycin, and the antifungal is butoconazole.
 5. The sustainedrelease composition of claim 1, wherein said sustained releasecomposition is formulated in a semisolid form.
 6. The sustained releasecomposition of claim 5, wherein the semisolid form is a gel, a cream, apaste, a lotion, an ointment, a shampoo, a semisolid powder or asuspension.
 7. The sustained release composition of claim 1, wherein thesilica microspheres have a mean microsphere size in the range of 0.5micron to 40 microns.
 8. The sustained release composition of claim 1,further comprising one or more of a solvent, a preservative, anemulsifier, an emollient or humectant, and water.
 9. The sustainedrelease composition of claim 8, wherein the solvent is selected from thegroup consisting of isopropanol, oleic acid, glycerol monooleate, oleylalcohol, propylene glycol, isopropyl myristate, and combinationsthereof.
 10. The sustained release composition of claim 1, wherein thecomposition treats vulvar and vaginal atrophy, bacterial vaginosis andbacterial infections, or vulvovaginal candidiasis.
 11. A method oftreatment of the vaginal area, the method comprising: providing asustained release vaginal composition for topical applicationcomprising: 0.001 to 15.0% w/w of an active ingredient selected from asteroid, an antibiotic, an antifungal, and combinations thereof; andsilica microspheres, formed prior to contact with the active ingredient,impregnated with the active ingredient; applying the sustained releasevaginal composition to the vaginal area as a single dose when the activeingredient is an antifungal or once daily for at most 14 days when theactive ingredient is a steroid or an antibiotic.
 12. The method of claim11, wherein the active ingredient comprises the steroid, the steroidcomprising estradiol, and wherein the method treats vulvar and vaginalatrophy.
 13. The method of claim 11, wherein the active ingredientcomprises the antibiotic, the antibiotic comprising metronidazole and/orclindamycin, and wherein the method treats bacterial vaginosis andbacterial vaginal infections and/or vulvovaginal candidiasis.
 14. Themethod of claim 11, wherein the active ingredient comprises theantifungal, the antifungal comprising butoconazole, and wherein themethod treats vulvovaginal candidiasis.
 15. The method of claim 11,wherein some of the active ingredient is free in the composition, andthe active ingredient impregnated in the silica microspheres providessustained release of the active ingredient.
 16. The method of claim 11,wherein the active ingredient is present as 0.001 to 5% w/w of thecomposition.
 17. The method of claim 11, wherein applying the sustainedrelease vaginal composition comprises topical application of a semisolidform of the sustained release vaginal composition.
 18. The method ofclaim 17, wherein the semisolid form is a gel, a cream, a paste, alotion, an ointment, a shampoo, a semisolid powder or a suspension. 19.The method of claim 11, wherein the silica microspheres have a meanmicrosphere size in the range of 0.5 micron to 40 microns.
 20. Themethod of claim 11, wherein the said sustained release vaginalcomposition further comprises one or more of a solvent, a preservative,an emulsifier, an emollient or humectant, and water.